Biology subjects

Sanderson, M.

Publications and source records attributed to Sanderson, M..

3 recordsLinked to original sources

bioRxiv2022

Mouse and cellular models of KPTN-related disorder implicate mTOR signalling in cognitive and progressive overgrowth phenotypes

KPTN-related disorder (KRD) is an autosomal recessive disorder associated with germline variants in KPTN (kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KRD, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn-/- mice display many of the key KRD phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. Assessment of affected individuals has identified concordant selectivity of cognitive deficits, postnatal onset of brain overgrowth, and a previously unrecognised KPTN dosage-sensitivity, resulting in increased head circumference in their heterozygous parents. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape, and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated iPSC models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. Increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KRD in the broader group of mTORC1 related disorders affecting brain structure, cognitive function, and network integrity.

genetics↗

bioRxiv2020

A new (old) approach to genotype-based phylogenomic inference within species, with an example from the saguaro cactus (Carnegiea gigantea)

AO_SCPLOWBSTRACTC_SCPLOWGenome sequence data are routinely being used to infer phylogenetic history within and between closely related diploid species, but few tree inference methods are specifically tailored to diploid genotype data. Here we re-examine the method of "polymorphism parsimony" (Inger 1967; Farris 1978; Felsenstein 1979), originally introduced to study morphological characters and chromosome inversion polymorphisms, to evaluate its utility for unphased diploid genotype data in large scale phylogenomic data sets. We show that it is equivalent to inferring species trees by minimizing deep coalescences--assuming an infinite sites model. Two potential advantages of this approach are scalability and estimation of a rooted tree. As with some other single nucleotide polymorphism (SNP) based methods, it requires thinning of data sets to statistically independent sites, and we describe a genotype-based test for phylogenetic independence. To evaluate this approach in genome scale data, we construct intraspecific phylogenies for 10 populations of the saguaro cactus using 200 Gbp of resequencing data, and then use these methods to test whether the population with highest genetic diversity corresponds to the root of the genotype trees. Results were highly congruent with the (unrooted) trees obtained using SVDquartets, a scalable alternative method of phylogenomic inference.

evolutionary biology↗

bioRxiv2020

Terraces in Gene Tree Reconciliation-Based Species Tree Inference

AO_SCPLOWBSTRACTC_SCPLOWTerraces in phylogenetic tree space are sets of trees with identical optimality scores for a given data set, arising from missing data. These were first described for multilocus phylogenetic data sets in the context of maximum parsimony inference and maximum likelihood inference under certain model assumptions. Here we show how the mathematical properties that lead to terraces extend to gene tree - species tree problems in which the gene trees are incomplete. Inference of species trees from either sets of gene family trees subject to duplication and loss, or allele trees subject to incomplete lineage sorting, can exhibit terraces in their solution space. First, we show conditions that lead to a new kind of terrace, which stems from subtree operations that appear in reconciliation problems for incomplete trees. Then we characterize when terraces of both types can occur when the optimality criterion for tree search is based on duplication, loss or deep coalescence scores. Finally, we examine the impact of assumptions about the causes of losses: whether they are due to imperfect sampling or true evolutionary deletion.

evolutionary biology↗